Visual cortex stability and plasticity in the absence of functional cones in achromatopsia

Hoffmann, Michael B.; Molz, Barbara; Herbik, Anne; Best, Peter de; Raz, Noa; Gouws, André; Ahmadi, Khazar; Lowndes, Rebecca; McLean, Rebecca J.; Kohl, Susanne; Gottlob, Irène; Choritz, Lars; Maguire, John F.; Kanowski, Martin; Käsmann‐Kellner, Barbara; Wieland, Ilse; Banin, Eyal; Levine, Netta; Basler, Heidi; Morland, Antony

doi:10.1167/jov.21.9.2062

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“…In adult patients with ACHM there is evidence for altered structure and function of cortex that normally processes cone information. 11 , 12 Detrimental effects of early visual deprivation have been shown to become more entrenched with age. 13 , 14 Therefore, it is plausible that the cortical capacity for processing new cone signals becomes increasingly limited with advancing age.…”

Section: Introductionmentioning

confidence: 99%

A demonstration of cone function plasticity after gene therapy in achromatopsia

Farahbakhsh

Anderson

Maimon-Mor

et al. 2022

Brain

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Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms’ reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10–15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies.

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